Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/76—Benzo[c]pyrans

Definitions

• the present invention relates to an advantageous method for producing isochroman-3-ones.
• Isochroman-3-one is in the synthesis of pharmaceuticals and pesticides as an intermediate product of great interest.
• WO 97/12864 describes the use of isochroman-3-one as an intermediate in the manufacture of fungicides and pesticides.
• the quality of traditional chemical processes is usually due to that Space / time yield given.
• catalytic chemical processes usually the catalytic change number (so-called “turnover number” or “TON”, i.e. the value that indicates how often a catalyst particle is used in the reaction ) and the catalytic alternating frequency (so-called “turnover frequency” or “TOF” i.e. the value that indicates how often a catalyst particle in an hour the reaction is used) as a quality feature.
• TON and TOF in comparison with the space / time yield give additional information about the Quality of the catalyst used in the reaction.
• the disadvantage is that the ortho-bromomethylbenzyl alcohol required as the starting material is not easily accessible.
• the use of potassium carbonate makes it difficult to carry out the process easily (release of CO 2 ).
• a comparatively long response time has to be accepted.
• WO 97/00850 A1 discloses a two-stage process for the preparation of isochroman-3-one derivatives, first of all a 1,2-bis-halomethylbenzene derivative of the general formula (A) wherein R is H, a halogen, a C 1 -C 6 alkyl or C 1 -C 6 alkory radical and X is a halogen, carbon monoxide and water are reacted in the presence of a hydrogen halide uptake agent and a catalyst in an organic solvent and the intermediate salt of ortho-hydroxymethylphenylacetic acid of the general formula (B), in which M represents an alkali or alkaline earth metal and n represents 1 or 2 then treated with an acid and converted into the corresponding isochroman-3-one.
• A 1,2-bis-halomethylbenzene derivative of the general formula (A) wherein R is H, a halogen, a C 1 -C 6 alkyl or C 1 -C 6 alkory radical and X is a halogen
• Palladium, cobalt and iron catalysts are suitable as catalysts.
• Bases in particular inorganic bases, for example calcium hydroxide, are used as the hydrogen halide uptake agent.
• hydrochloric acid for example, is used as the acid in order to bring about the conversion of the salt of the ortho-hydroxymethylphenylacetic acid derivative of the formula (B) into the corresponding isochroman-3-one.
• a yield of up to 87.4% of isochroman3-one can be achieved by this process, but a comparatively small amount of 8.75 g of ⁇ , ⁇ '-ortho-xylylene dichloride (1,2-bis-chloromethylbenzene) in not less than 100 g of tert-butanol is reacted.
• the present invention has for its object a new method of manufacture Isochroman-3-ones to provide, on the one hand with comparative can perform little effort, on the other hand, the disadvantages described above avoids the prior art processes and the desired product good yield and high purity.
• the process according to the invention makes it possible to implement the 1,2-bis-halomethylbenzene of the formula (II) in concentrations which are significantly higher than in the process according to WO 97/00850 A1.
• the space / time yield is advantageously increased and technical implementation is favored to a corresponding extent.
• Another advantage is that, compared to the process of WO 97/00850 A1, the salt of the formula (B) does not have to be formed and the second reaction step with the addition of acid can be dispensed with.
• the radicals R 1 , R 2 , R 3 and R 4 are, in particular independently of one another, hydrogen, fluorine, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy or two of the radicals R 1 , R 2 , R 3 and R 4 are linked together and form an aliphatic or aromatic ring with 5 to 10 carbon atoms.
• R 1 , R 2 , R 3 and R 4 are preferably independently of one another hydrogen, fluorine or C 1 -C 4 -alkyl.
• the procedure can be carried out in the presence or absence an ionic halide.
• the ionic halide is an alkali, ammonium or Phosphonium halide, especially an alkali or ammonium halide, where Halide means chloride, bromide or iodide, especially chloride or Bromide, preferably chloride.
• a palladium catalyst based on a Contain the palladium applied has the advantage that it consists of the reaction mixture, can be easily separated, for example by filtration.
• the palladium catalyst has at least one palladium (II) compound, in particular PdCl 2 , PdBr 2 or Pd (OAc) 2, preferably PdCl 2 , or at least one palladium (0) compound, in particular Pd 2 dba 3 , where dba stands for dibenzylidene acetone, contains Pd (P (C 6 H 5 ) 3 ) 4 or Pd ( ⁇ 4 -C 8 H 12 ) 2 , preferably Pd 2 dba 3 .
• the Palladium catalyst additionally a ligand, especially one Contains phosphine compound.
• phosphine compounds are a monophosphine, in particular a tri- (C 1 -C 6 -alkyl) phosphine or a triarylphosphine, or a diphosphine.
• the palladium catalyst contains one Bis (triphenylphosphine) palladium (II) compound, for example Bis (triphenylphosphine) palladium (II) chloride or bis (triphenylphosphine) palladium (II) bromide.
• Bis (triphenylphosphine) palladium (II) compound for example Bis (triphenylphosphine) palladium (II) chloride or bis (triphenylphosphine) palladium (II) bromide.
• the palladium catalyst is usually set in an amount of 0.00001 to 0.3 mol of palladium, in particular 0.000025 to 0.2 mol of palladium, preferably 0.00005 to 0.1 mole of palladium per mole of 1,2-bis-halomethylbenzene.
• the reaction can usually be carried out at a temperature of 50 to 170 ° C., perform in particular 70 to 160 ° C, preferably 90 to 150 ° C with good success.
• Suitable dipolar aprotic solvents are dioxane, tetrahydrofuran, an N- (C 1 -C 18 alkyl) pyrrolidone, ethylene glycol dimethyl ether, a C 1 -C 4 alkyl ester of an aliphatic C 1 -C 6 carboxylic acid, a C 1 -C 6 - Dialkyl ether, an N, N-di (C 1 -C 4 alkyl) amide of an aliphatic C 1 -C 4 carboxylic acid, sulfolane, a 1,3-di (C 1 -C 8 alkyl) -2- imidazolidinone, an N- (C 1 -C 8 alkyl) caprolactam, an N, N, N ', N'-tetra- (C 1 -C 8 alkyl) urea, a 1,3-di- (C 1 -C 8 alkyl) -3,4,5,6-tetra
• the 1,2-bis-halomethylbenzene of the formula (II), the palladium catalyst, the dipolar aprotic solvent and optionally the ionic halide sets the CO pressure and temperature and then doses water or a mixture consisting of water and dipolar aprotic solvent to.
• the mix is well mixed Reaction partners to ensure a rapid course of the reaction.
• the inventive method is suitable for both a continuous and also discontinuous implementation.
• the H 0 value which is a measure of the acidity of a solvent and for which H 0 ⁇ pH applies to dilute solutions, is in the Hollemann-Wiberg "Textbook of Inorganic Chemistry", 91-100. Edition, published by Walter de Gruyter, Berlin 1985, on pages 246-248. Kislina et al. describe for example the acidity of HCl in N, N-dimethylformamide in carbon black. Chem. Bull., 1994, Vol. 43, on pages 960-963 As a rule, the corresponding H 0 value sets itself up in the course of a reaction, so that additional measures for setting the H 0 value are usually not necessary are.
• H 0 pK S, In + logC In / C InH + (Hammett's acidity function) .
• In stands for the indicator base and InH + for the protonated form of the indicator base.
• reaction mixture 2065 g of reaction mixture are obtained.
• the reaction mixture is in a thin film evaporator at 100 ° C and 10 mbar 733 g of low boilers separated.
• Carbon monoxide is then added at a pressure of 3 MPa and the temperature increased to 130 ° C.
• the reaction pressure is during the The reaction time was kept between 3.5 and 4.0 MPa. After a reaction time of 3 hours is allowed to stir for an hour, cooled to 90 ° C and emptied the autoclave.
• reaction mixture 150 g of reaction mixture are obtained.
• the temperature is then raised to 70 ° C. under a carbon monoxide atmosphere elevated.
• the carbon monoxide uptake started with vigorous stirring at 60 ° C is finished after 2 hours and you get a viscous porridge.
• the addition of a further 1.05 g of bis (triphenylphosphine) palladium (II) chloride and 0.87 g Triphenylphosphine leads to no further carbon monoxide uptake.
• Carbon monoxide is then added at a pressure of 3.0 MPa and the temperature increased to 130 ° C.
• pressure 32.5 ml of water / N-methylpyrrolidone (weight ratio 1: 5) metered. After dosing, cool to 75 ° C and relax Autoclaves.
• reaction mixture 162 g of reaction mixture are obtained.
• Carbon monoxide is then added at a pressure of 1.7 MPa and the temperature increased to 130 ° C.
• pressure is within 15 ml of water / dimethylformamide (weight ratio 1: 4) were metered in for 5 hours. After the metering is allowed to stir for an hour and the autoclave is relaxed. Then 15 ml of water are added and the mixture is left under stirring Cool down to room temperature.
• Carbon monoxide is then added at a pressure of 3.0 MPa and the temperature increased to 130 ° C.
• pressure 53 ml water / N, N-dimethylformamide within 5.6 hours (1: 1 weight ratio) metered. After dosing, you cool off and relaxes the autoclave.
• reaction mixture 222 g of reaction mixture are obtained.
• Carbon monoxide is then added at a pressure of 16.0 MPa and raised the temperature to 150 ° C.
• pressure becomes 7.2 ml of water / N-methylpyrrolidone within 230 minutes (1: 1 weight ratio) metered. Then you stop the experiment by it is relaxed and cooled to 50 ° C. within 15 minutes.
• reaction mixture 150 g of reaction mixture are obtained.
• Carbon monoxide is then added at a pressure of 16.0 MPa and raised the temperature to 150 ° C.
• pressure becomes 7.2 ml of water / N-methylpyrrolidone within 230 minutes (1: 1 weight ratio) metered. Then you stop the experiment by it is relaxed and cooled to 50 ° C. within 15 minutes.
• reaction mixture 1301 g are obtained.

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• Chemical & Material Sciences (AREA)
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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Pyrane Compounds (AREA)

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• 1998
  • 1998-04-06 DE DE19815323A patent/DE19815323C2/de not_active Expired - Fee Related
• 1999
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  • 1999-03-17 EP EP99105411A patent/EP0949256B1/fr not_active Expired - Lifetime
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